A significant body of research supports a role of vascular disease in the pathogenesis of late-life depression. It has been proposed that vascular disease affects white matter pathways and subcortical structures involved in mood regulation and is associated with poorer cognitive function and treatment resistance. While a number of cross-sectional observations have been described, it is not known how these abnormalities predict longitudinal course. Further, the interaction between white matter pathology and structural changes in important gray matter structures, including orbitofrontal cortex, amygdala, hippocampus and basal ganglia is not fully studied. The proposed study will follow up a well defined cohort of late life depressed (LLD) subjects recruited for the NIH-funded "Treatment Outcome of Vascular Depression" study. In that study we have found an association between baseline cognitive and structural measures and acute response to antidepressants. In the current proposal we will extend those findings to determine their impact on longitudinal course of depression. The proposed study will examine the effect of baseline neuroimaging findings and cognitive function in predicting course of illness over a five year follow-up. We propose to conduct a collaborative study with 168 elderly subjects enrolled in the previous "Treatment Outcomes of Vascular Depression" study at Duke University and Washington University. They will receive follow-up magnetic resonance imaging, neuropsychological testing, and a careful interval history focusing on their depression history, antidepressant use, and medical history to test the hypotheses that: 1) LLD individuals with more depressive episodes over the 5 year longitudinal course will have greater baseline impairment on measures of a) white matter structure b) smaller volumes of the amygdala, hippocampus, and orbitofrontal cortex and c) neuropsychological function; 2) LLD individuals with more depressive episodes over the 5 year longitudinal course will have greater changes on these MRI and neuropsychological test variables over the interim. In secondary aims we will test the effect of the interaction of the measures on depression duration, and examine the effects of connectivity in specific fiber tracts on depression course. The proposal will provide important new data on neuroradiologic and neuropsychological factors contributing to recurrent or chronic depression in older individuals. [unreadable] [unreadable] [unreadable] [unreadable]